RT Journal Article SR Electronic T1 Tob Regulates the Timing of Sleep Onset at Night in Drosophila JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP e0389232024 DO 10.1523/JNEUROSCI.0389-23.2024 VO 44 IS 18 A1 Han, Emily A1 Lee, Sang Soo A1 Park, Kristen H. A1 Blum, Ian D. A1 Liu, Qiang A1 Mehta, Anuradha A1 Palmer, Isabelle A1 Issa, Habon A1 Han, Alice A1 Brown, Matt P. A1 Sanchez-Franco, Victor M. A1 Velasco, Miguel A1 Tabuchi, Masashi A1 Wu, Mark N. YR 2024 UL http://www.jneurosci.org/content/44/18/e0389232024.abstract AB Sleep is regulated by homeostatic sleep drive and the circadian clock. While tremendous progress has been made in elucidating the molecular components of the core circadian oscillator, the output mechanisms by which this robust oscillator generates rhythmic sleep behavior remain poorly understood. At the cellular level, growing evidence suggests that subcircuits in the master circadian pacemaker suprachiasmatic nucleus (SCN) in mammals and in the clock network in Drosophila regulate distinct aspects of sleep. Thus, to identify novel molecules regulating the circadian timing of sleep, we conducted a large-scale screen of mouse SCN-enriched genes in Drosophila. Here, we show that Tob (Transducer of ERB-B2) regulates the timing of sleep onset at night in female fruit flies. Knockdown of Tob pan-neuronally, either constitutively or conditionally, advances sleep onset at night. We show that Tob is specifically required in “evening neurons” (the LNds and the fifth s-LNv) of the clock network for proper timing of sleep onset. Tob levels cycle in a clock-dependent manner in these neurons. Silencing of these “evening” clock neurons results in an advanced sleep onset at night, similar to that seen with Tob knockdown. Finally, sharp intracellular recordings demonstrate that the amplitude and kinetics of LNd postsynaptic potentials (PSPs) cycle between day and night, and this cycling is attenuated with Tob knockdown in these cells. Our data suggest that Tob acts as a clock output molecule in a subset of clock neurons to potentiate their activity in the evening and enable the proper timing of sleep onset at night.